Abstract
Recent studies claim a critical role for RUNX3 in gastric epithelial homeostasis. However, conflicting results exist regarding RUNX3 expression in the stomach and its potential role as a tumour-suppressor gene (TSG) in gastric carcinogenesis. Our aim was to evaluate the role of RUNX3 in early-onset gastric carcinomas (EOGCs). We analysed 41 EOGCs for RUNX3 aberrations using loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) analyses. LOH of markers flanking RUNX3 was relatively common, indicating that loss of the gene may play a role in gastric carcinogenesis. However, FISH analysis of selected cases and a panel of 14 gastric carcinoma-derived cell lines showed widespread presence of multiple copies of centromere 1. While RUNX3 copy numbers were generally equal to or fewer than those of centromere 1, at least two copies were present in almost all cells analysed. Accordingly, a subpopulation of tumour cells in 12/37 cases showed RUNX3 protein expression. However, expression was not detected in the adjacent nontumorous mucosa of any case. Together, these observations indicate that chromosome 1 aberrations occur frequently in EOGCs and are reflected in the LOH and IHC patterns found. Our findings refute a role for RUNX3 as a TSG in EOGCs.
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Acknowledgements
We thank Dr D Levanon and Dr Y Groner (The Weizmann Institute of Science, Israel) for the invaluable assistance with RUNX3 IHC detection and analysis. We also thank Alex Musler, Folkert Morsink, Monique Oud and Esther Schilder (Academisch Medisch Centrum, The Netherlands) for the technical assistance provided. We further wish to acknowledge Dr S Akiyama (Nagoya University School of Medicine, Japan), Dr JN Primrose (Southampton General Hospital, UK), Dr H Yokozaki (Hiroshima University School of Medicine, Japan), Professor T Suzuki (Fukushima Medical College, Japan), Dr K Yanagihara (National Cancer Centre Research Institute, Japan), Dr M Manns (Medizinische Hochschule Hannover, Germany), Dr A van der Ende (Academisch Medisch Centrum, The Netherlands) and Professor M Sobrinho-Simões (Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Portugal) for kindly providing the cell lines used in this study. Finally, we wish to thank Dr A Varis and Dr S Knuutila (both from the University of Helsinki, Finland) for their FISH expertise and their many helpful suggestions. This work was supported by the Vanderes Foundation, grant 68.
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Carvalho, R., Milne, A., Polak, M. et al. Exclusion of RUNX3 as a tumour-suppressor gene in early-onset gastric carcinomas. Oncogene 24, 8252–8258 (2005). https://doi.org/10.1038/sj.onc.1208963
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DOI: https://doi.org/10.1038/sj.onc.1208963
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